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Products of the Reaction of Phenyihydrazine With Proc. NatL Acad. Sci. USA Vol. 78, No. 9, pp. 5508-5512, September 1981 Biochemistry (3meso-Phenylbiliverdin IXa and N-phenylprotoporphyrin IX, products of the reaction of phenyihydrazine with oxyhemoproteins (neso-tolylbiliverdin/N-tolylprotoporphyrin/Heinz body anemia/oxyhemoglobin/oxymyoglobm) SETSUO SArrO AND HARVEY A. ITANO Department of Pathology, D-006, University of California, San Diego, La Jolla, California 92093 Contributed by Harvey A. Itano, June 12, 1981 ABSTRACT Oxyhemoglobin and oxymyoglobin were allowed EXPERIMENTAL PROCEDURES to react aerobically with phenylhydrazine and p-tolylhydrazine. The chloroform extract ofeach reaction mixture, after treatment Materials and Methods. To a solution of metmyoglobin (5 with H2SOdmethanol, yielded a blue pigment and a.green pig- g, type III from horse heart, Sigma) in potassium phosphate ment, which were identified by electronic absorption, mass, and buffer (pH 7.4, 0.01 M, 200 ml), a 50-fold excess of powdered proton NMR spectroscopy as the dimethyl esters of -mao-ar- Na2S204 was added under N2. This mixture was applied onto ylbiliverdin IXa and N-arylprotoporphyrin IX, respectively. N- a column of Sephadex G-25 (5 cm inside diameter x 30 cm) Phenyiprotoporphyrin IX dimethyl ester formed complexes, with equilibrated with phosphate buffer (pH 7.4, 0.01 M) and was Zn2+, Cd'+, and Hg'+ but not with other cations. The proton eluted from the column with the same buffer. The eluate was NMR spectrum of the zinc complex suggested binding of the dialyzed against phosphate buffer (pH 7.4, 0.1 M, 4 liters) to phenyl group to one ofthe two pyrrole rings ofprotoporphyrin IX obtain a solution ofoxymyoglobin (3.58 g, 72% yield). Washed with a propionic acid substitutent. The effectiveness ofphenylhy- human erythrocytes were lysed with 3 vol ofdistilled water and drazine as an inducer ofHeinz body formation may be due to de- centrifuged at 12,000 X g for 90 min to obtain a clear solution stabilization of the hemoglobin. molecule by the replacement of of hemolysate. This solution was dialyzed against phosphate heme with phenyl adducts ofbiliverdin and protoporphyrin. buffer (pH 7.4, 0.1 M, 4 liters), and the resulting dialysate was used for reactions of oxyhemoglobin. Biliverdin IX, obtained The green hemoglobin produced in the reaction ofhemoglobin by coupled oxidation ofhemin, myoglobin, or hemoglobin with with phenylhydrazine was found by Kiese and Seipelt (1) to ascorbic acid (7, 8), was esterified in 7% H2SO4 in methanol. * differ from verdoglobins produced by other reagents. Lemberg The isomers ofbiliverdin IX dimethyl ester were separated by and Legge (2) showed that biliverdin production was increased thin-layer chromatography (TLC) (9). Phenylhydrazine-HCl in the erythrocytes ofrabbits treated with phenylhydrazine, and and p-tolylhydrazine HCl (Aldrich) were recrystallized from they concluded that this in vivo result of phenylhydrazine ac- ethanol before use. SilicAR cc-7 Special (Mallinckrodt) was used tivity corresponded to the in vitro formation ofbiliverdin in the for column chromatography. Uniplate (Silica Gel G, Analtech) coupled oxidation ofhemoglobin and ascorbic acid. Beaven and was used for analytical and preparative TLC. Electron impact White (3), on the other hand, did not obtain biliverdin in the mass spectra were obtained on an LKB type 9000 spectrometer in vitro reaction of phenylhydrazine with oxyhemoglobin; in- at an ionizing energy of70 eV by the direct inlet method. Field stead they isolated a green pigment with an absorption band in desorption mass spectra were obtained on a Kratos/AEI MS- the Soret region suggestive of an intact porphyrin ring. 902 instrument. Optical spectra were recorded on a Cary model Studies from this laboratory indicated that substituents on 17 spectrophotometer. Proton nuclear magnetic resonance the benzene ring affected the hemolytic activity of substituted (NMR) spectra of samples in C2HC13 solution containing inter- phenylhydrazine and the binding ofsubstituted phenyldiazenes nal tetramethylsilane were recorded with a custom-designed to methemoglobin in parallel fashion (4). Subsequent studies 360-MHz spectrometer with 200-400 pulses in the Fourier- showed, however, that the hemolytic activity of ring-substi- transform mode. High-performance liquid chromatography was tuted nitrosobenzenes was not related to their affinities as li- carried out with the Altex model 334 system. A Whatman Par- gands ofdeoxyhemoglobin (5). tisil 10-PAC column (4.6 x 250 mm) preceded by a short Partisil A two-electron transfer to oxyhemoglobin was suggested as 10 protective precolumn was used. Mass spectra of the four the initial step in the degradation ofheme mediated by ascorbic isomers ofbiliverdin IX dimethyl ester and the NMR spectrum acid (6), and the same transfer was postulated in the reaction of biliverdin IXa dimethyl ester were obtained for use as ofphenylhydrazine with oxyhemoglobin (4). Although the pro- standards. cesses may be initiated in the same way, different reported Blue (I) and Green (II) Pigments from the Reaction ofPhen- products, biliverdin with ascorbic acid (2) and an intact por- ylhydrazine with Oxymyoglobin. A solution of phenylhydra- phyrin with phenyihydrazine (3), indicate that subsequent steps zine-HCl (188 mg) in phosphate buffer (pH 7.4, 0.1 M, 100 ml) are different. We therefore undertook to isolate and character- was added to 500 ml of260 jLM oxymyoglobin in the same buf- ize the products of heme degradation when hemoglobin is fer, and the reaction mixture was allowed to stand for 1 hr under treated with arylhydrazines, and we found two types of com- aerobic conditions with occasional shaking. Acetic acid (400 ml) pounds: one is a biliverdin IXa derivative with an aryl group and concentrated HC1 (100 ml) were then added to 0C. After on a meso carbon, and the other is a protoporphyrin IX deriv- 20 hr at 40C, the reaction mixture was extracted twice with chlo- ative with an aryl group on a pyrrole nitrogen. roform (300 ml and 150 ml). The extracts were gathered, washed The publication costs ofthis article were defrayed in part by page charge Abbreviations: TLC, thin-layer chromatography; Fe", deoxyhemopro- payment. This article must therefore be hereby marked "advertise- tein; FeII02, oxyhemoprotein. ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. * All reagent percentages and solvent ratios are vol/vol. 5508 Downloaded by guest on October 1, 2021 Biochemistry: Saito and Itano Proc. Natd Acad. Sci. USA 78 (1981) 5509 with distilled water, dried over anhydrous Na2SO4, filtered, and globin (227 pM) in phosphate buffer (pH 7.4, 0.1 M, 600 ml), evaporated to obtain residue A (99.5 mg, 59.9% yield from a solution ofphenylhydrazine-HCl (800 mg) in the same buffer phenylprotoporphyrin, Mr 638). A solution ofthis residue in 7% (100 ml) was added. The procedure described above to obtain H2S04 in methanol (100 ml) at 0C was allowed to stand for 18 residue A was used to obtain residue C (405 mg, 57.3% yield hr at 4TC, diluted with cold distilled water (150 ml), and ex- from phenylprotoporphyrin, Mr 638). The crude product from tracted twice with chloroform (200 ml and 100 ml). The extracts the treatment of residue C with 7% H2SO4 in methanol was were treated as described above to obtain a residue that showed applied onto a silica gel column (5 cm inside diameter X 20 cm) a minor blue spot (RF: 0.47 in 4:1 benzene/acetone, 0.90 in 22:3 and eluted with the following solvents: 100% chloroform (200 chloroform/ethanol), a major green spot (RF: 0.02 in 4:1 ben- ml), 5% acetone in chloroform (200 ml), 5% methanol in chlo- zene/acetone, 0.20 in 22:3 chloroform/ethanol), and some roform (200 ml), and 10% methanol in chloroform (400 ml). The brown spots by TLC. The residue was applied onto a silica gel 5% acetone eluate was evaporated to give a residue that showed column (1.5 cm inside diameter x 12 cm) and eluted in succes- a major blue spot (RF: 0.47 in 4:1 benzene/acetone and a minor sion with the following solvents: 100% chloroform (100 ml), 3% blue spot (RF: 0.53 in 4:1 benzene/acetone) that overlapped a acetone in chloroform (50 ml), 5% acetone in chloroform (50 ml), brown spot by TLC. The major blue pigment (43mg, 9.9% from 5% methanol in chloroform (150 ml), and 10% methanol in chlo- residue C) was isolated and purified by preparative TLC. This roform (300 ml). The 5% acetone eluate was evaporated to ob- blue pigment was the same as pigment I obtained from the re- tain a blue oil (I, 13 mg, 12% yield from residue A), which was action of oxymyoglobin with phenylhydrazine according to its further purified by preparative TLC (silica gel, 4:1 benzene/ TLC behavior, electronic absorption spectrum, and NMR spec- acetone) for spectral determinations. Mass spectrum m/e (rel- trum. The 10% methanol eluate was evaporated to give a res- ative intensity): 686 (parent ion M+, 2.0), 567 (14.0), 478 (3.6), idue from which a green pigment (184 mg, 43.5% yield from 404 (3.6), 402 (3.4), 390 (56.8), 376 (100), 361 (4.5), 359 (3.6), residue C) was isolated by preparative TLC. The TLC and spec- 347(4.0), 345 (5.9), 317 (20.5), 314 (9.8), 303 (20.0), 300 (36.0), tral properties of this green pigment were the same as those of 287 (50.0), 241 (22.7), 227 (40.9), 199 (27.3), 181 (22.6), 180 pigment II from the reaction of oxymyoglobin with (22.7), 122 (22.7), 155 (13.6), 108 (40.9). NMR spectrum (in phenylhydrazine. C2HC13; 6 in ppm; m, multiplet; s, singlet) 6: 1.60 (CH3), 1.94 Zinc Complex of Green Pigment II.
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